This invention relates to in vivo monitoring one or more solutes in a biological system using optical techniques.
Monitoring the concentration of a solute (e.g., low molecular weight carbohydrate or polyhydroxy compounds such as sugars (mannitol, sorbitol, fructose, sucrose, or glucose), alcohols (methanol, ethanol, or propanediol), and electrolytes (sodium, potassium, magnesium, calcium, or chloride ions)) in a biological system has important applications in the medical field. For example, it is important for diabetics, who have gone off insulin, to monitor their glucose level so that can remedy any serious deviation in the level before harm occurs.
Near infra-red radiation (NIR) has been used to study non-invasively the oxygen metabolism in tissue (for example, the brain, finger, or ear lobe). Using visible, NIR and infra-red (IR) radiation for medical imaging could bring several advantages. In the NIR or IR range the contrast factor between a tumor and a tissue is much larger than in the X-ray range. In addition, the visible to IR radiation in preferred over the X-ray radiation since it is non-ionizing; thus, it potentially causes fewer side effects. However, with lower energy radiation, such as visible or infra-red radiation, the radiation is strongly scattered and absorbed in biological tissue, and the migration path cannot be approximated by a straight line, making inapplicable certain aspects of cross-sectional imaging techniques.
In a general aspect, the invention features a scheme for monitoring one (or more) solute in a biological system comprising the steps of: delivering light into a biological system containing one (or more) solute, the light having a wavelength selected to be in a range wherein the one (or more) solute is substantially non-absorbing; detecting at least first and second portions of the delivered light, the first portion having traveled through the biological system along one or more paths characterized by a first average path length, and the second portion having traveled through the biological system along one or more paths characterized by a second average path length that is greater than the first average path length; and comparing the first and second portions of the delivered light to monitor concentration of the one (or more) solute in the biological system.
Embodiments of the invention may include one or more of the following features. Comparing the first and second portions of the delivered light preferably comprises obtaining a characterization of the biological system based on a linear model relating an optical characteristic of the biological system and the first and second average path lengths. The characterization that is obtained may be the slope and/or the intercept of a line determined by fitting to the linear model measured characteristics of the first and second portions of light and distances representative of the first and second path lengths. Obtaining a characterization may comprise obtaining measures of first and second optical densities of the biological system based on the first and second portions of detected light and fitting the measures of optical densities to the generally linear model. Comparing the first and second portions of the delivered light may comprise determining a measure of the concentration of one or more of the solutes based on a comparison of the characterization of the biological system against a predetermined scale.
The monitoring scheme may further comprise determining a measure of a concentration of one or more of the solutes in the biological system based on a predetermined concentration scale. Detecting the first and second portions of the delivered light preferably comprises measuring first and second intensities (I1, I2) corresponding to the intensities of the first and second portions of light, respectively.
The monitoring scheme may further comprise determining changes, over time, in the first and second intensities (I1, I2) relative to first and second reference intensities (I1,ref, I2,ref). Determining relative changes in the first and second intensities may further comprise respectively determining first and second optical densities (OD1, OD2):             OD      1        =          log      ⁢              (                              I            1                                I                          1              ,              ref                                      )                        OD      2        =                  log        ⁢                  (                                    I              2                                      I                              2                ,                ref                                              )                    .      
Comparing the first and second portions of the delivered light may comprise using a linear model relating the first and second optical densities to distances (xcfx811, xcfx812) representative of the first and second average path lengths to obtain a characterization of the biological system representative of the concentration of one or more of the solutes in the biological system. The characterization that is obtained in a slope (m) may be determined by   m  =                              OD          2                -                  OD          1                                      ρ          2                -                  ρ          1                      .  
The characterization that is obtained may be an intercept (b) determined by   b  =                                          OD            1                    ·                      ρ            2                          -                              OD            2                    ·                      ρ            1                                                ρ          2                -                  ρ          1                      .  
The monitoring scheme may further comprise detecting a third portion of the delivered light, the third portion having traveled through the biological system along one or more paths characterized by a third average path length that is greater than the first and second average path lengths.
In another aspect, the invention features a system for monitoring one or more solutes in a biological system comprising: at least two sources of light having a wavelength selected to be in a range wherein at least one of the one or more solutes is substantially non-absorbing, a detector positioned at different distances with respect to the at least two detectors to detect at least first and second portions of the delivered light, the first portion having traveled through the biological system along one or more paths characterized by a first average path length, and the second portion having traveled through the biological system along one or more paths characterized by a second average path length that is greater than the first average path length, and a comparator adapted to compare the first and second portions of the delivered light to monitor a concentration of one or more of the solutes in the biological system.
In one embodiment of the invention, two or more continuous light sources are used and light reflectance at separated input-output distances are measured. Approximation of the exact solution for the spatially resolved reflectance at separations larger than 2.5 cm provides a linear relationship between the separation and absorbance variation with respect to a reference sample. slope and intercept of this straight line are functions of the absorption and scattering coefficients (xcexca and xcexcsxe2x80x2) of the measured sample. Using this technique, high measurement sensitivities for solute concentrations in a biological system can be achieved. For example, absorbency changes of approximately 0.2 milli OD are obtained for a 1 millimolar concentration change of the solute and per 1% change of the intralipid concentration.
Solutes contained in a biological system respond to migrating near-infrared and infrared light by acting primarily to scatter the applied light. The signal intensity of such migrating light in affected to a greater extent the longer the average path length migrated by the detected light. This enables us to obtain a linear relationship between an optical parameter of the biological system and at least two distances representative of average path lengths traveled by the detected light through the biological system (e.g., at least two different source detector spacing).
Solutes include low molecular weight carbohydrates such as sucrose, glucose, mannitol, sorbitol, inositol, maltose, lactose, galactose, and glucuronic acid; and hydroxy-functionalized compounds such as alcohols (methanol, ethanol), phenols, catechols, and flavanoids (e.g., flavanones, flavones); and metabolites and metabolic precursors thereof. Solutes also include neurotransmitters such as amino acids (xcex3-aminobutyric acid, glycine, glutamate), choline, acetylcholine, norepinephrine, epinephrine, dopamine, serotonin, and histamines; and electrolytes (sodium, potassium, magnesium, calcium) and other soluble ions of the IA, IIA, and VIIB groups of the periodic table. Solutes are present in the interstitial spaces between cells, present within cells, or present in the blood (e.g., soluble in serum), or a combination thereof. They may be released from or taken up by cells as intra- or inter-cellular messengers, as metabolites (or byproducts), or as metabolic precursors or nutrients.
Solutes may be labelled with one or more radioisotopes of H, C, O, S, or P (e.g., 32P and tritium) or with a detectable agent (e.g., a contrast agent sensitive to a selected wavelength in the visible or infra-red range); or derivatized (e.g., deoxyglucose, or phosphoinositol). Solutes may thus be covalently linked to exogenous contrast agents; when linked to a detectable agent, either the solute or the agent may be measured or monitored according to the methods disclosed herein. For example, a wavelength may be selected such that a contrast agent is substantially non-absorbing, or a solute is substantially non-absorbing, or both.
Other features and advantages will become apparent from the following description and from the claims.